Antibodies Predict Scleroderma Renal Crisis

The presence of a specific group of autoantibodies in patients with scleroderma was associated with a high risk of renal crisis, Japanese researchers reported.

The scleroderma renal crisis occurred in 24% of patients who had anti-RNA polymerase III (RNAP III) antibodies but in only 1% of those without these autoantibodies, for an odds ratio of 21.6 (95% CI 7.8-60.3, P<0.00001), according to Manabu Fujimoto, MD, of the University of Tsukuba in Ibaraki, and colleagues.

And in a multivariate analysis that adjusted for relevant factors such as steroid use and modified Rodnan skin scores, positivity for all three subclasses of RNAP was independently associated with the development of renal crisis (OR 11, 95% CI 1.6-222.8, P=0.0118), the researchers reported online in Arthritis and Rheumatology.

Scleroderma renal crisis, characterized by acute progressive loss of kidney function and accelerated hypertension, is a particularly dangerous development associated with high mortality.

More than 90% of patients with scleroderma, also known as systemic sclerosis (SSc), have detectable antinuclear antibodies. Several types of these antibodies are SSc-specific, including antibodies against centromeres, topoisomerase I, and RNAP III.

"Importantly, antinuclear antibodies are closely associated with distinct clinical subsets, and thus detection of SSc-related antibodies is useful not only in the diagnosis, but also for predicting forthcoming organ involvement and prognosis," Fujimoto and colleagues wrote.

Some previous research has identified anti-RNAP III antibodies as being present in about one-third of patients with scleroderma who experienced renal crises, but more specific immunologic and clinical predictors within this group of patients have not previously been identified.

Therefore, Fujimoto and colleagues conducted an analysis of 583 patients seen between 1995 and 2012 at two Japanese centers.

Among the cohort, 60% had the limited cutaneous form of scleroderma, while the remainder had diffuse cutaneous disease. A total of 37 (6%) had positive ELISA assays for anti-RNAP III, and most of these had the diffuse cutaneous type.

On the immunoprecipitation assays for RNAP, 17 of the 37 patients were positive for all three classes of anti-RNAP (I/II/III), 19 were positive for the I and III forms, and one was positive only for anti-RNAP III. For the purposes of the analysis, the patient who was positive for only the III class was included with the I/II/III group.

Scleroderma renal crisis occurred in 17 patients (2.9%), nine of whom were anti-RNAP positive. Renal crisis also occurred in eight patients out of 546 who were anti-RNAP negative but had other autoantibodies such as anti-topoisomerase I.

Eight of the anti-RNAP-positive patients received corticosteroids, most often in dosages higher than 15 mg per day.

The researchers then compared clinical characteristics of the nine anti-RNAP-positive patients who developed scleroderma renal crisis with 28 antibody-positive patients who had no renal crisis, and found only nonsignificantly higher Rodnan skin scores in the renal crisis group (21 versus 17, P=0.2778).

There also was no difference in steroid doses, but significantly higher ELISA indexes, which were determined by the receiver operating characteristic curves for anti-RNAP III, were identified in the renal crisis group (250.4 versus 141.6, P=0.0013). In addition, the ELISA index showed a positive correlation with skin scores (R2=0.11365, P=0.0413).

In a univariate analysis, factors that were significantly associated with the occurrence of scleroderma renal crisis were positivity for anti-RNAP I/II/III, with an odds ratio of 16.9 (95% CI 1.8-156.3, P=0.0055) and the ELISA index for anti-RNAP III being above 157, with an odds ratio of 33.5 (95% CI 4.2-268.2, P<0.0001).

The ELISA index also remained significant, along with anti-RNAP I/II/III positivity, in the multivariate analysis.

The authors noted that ethnicity is an important factor in anti-RNAP-III positivity. In a U.S. cohort, 25% of patients were antibody positive, as were 15.3% of Australian patients and 4% of French patients. In a previous study of Japanese patients, the prevalence was 10.7%, similar to the 6% seen in this study, "confirming our previous finding that anti-RNAP III is more prevalent in North American than in Japanese SSc patients," the authors noted.

"Our findings should be confirmed in a large-scale study of patients of different ethnicities in future studies," they concluded.

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